UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: September 16, 2014 

SUBJECT: Metolachlor: Tier I Review of Human Incidents 

PC Code: 108801,108800 

Decision No.: 49150 I 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRIDNo.:NA 

OP Barcode: 042080 1 

Registration No.: NA 

Regulatory Action: NA 

Case No.: NA 

CAS No.: 51218-45-2, 87392-12-9 

40 CFR: NA 

Ver.Apr.08 

FROM: Elizabeth Evans, Environmental Protection Specialist ~~_Q 

j/)f' 

Shanna 

Carol Christensen, 

Recore, Ind

Ph.D., 

ustrial 

Epidemiologist.£1~VJ 

Hygienist ~ ~ 

L Toxicology and Epidemiology Branch ( 

Health Effects Division (7509P) 

1/,11~ !IJ~ -iliV THROUGH: David Miller, Acting Branch Chie{A._/LJ'/V t1. 

Toxicology and Epidemiology Branch 

Health Effects Division (7509P) 

TO: Jessica Kidwell, Risk Assessor 

Risk Assessment Branch IV 

Health Effects Division (7509P) 

and 

Kaitlin Keller, Chemical Review Manager 

Risk Management & Implementation Branch 3 

Pesticide Re-evaluation Division (7508P) 

Summary and Conclusions 

There does not appear to be a concern at this time that would warrant further investigation, since 

there is a low frequency of incidents involving metolachlor reported to IDS and SENSORPesticides. The Agency will continue to monitor the incident information and if a concern is 

triggered, additional analysis will be included in the risk assessment. AHS study results indicate 

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a possible association with lung cancer (observed in two studies within the cohort); however, 

chance and bias (exposure classification, exposure algorithm, and control for the effect of 

smoking) cannot be ruled out. EPA will continue to monitor this literature. 

Detailed Review 

I. ACTION REQUESTED 

This review is intended to fulfill our requirement to docket summaries of incident data that were 

reported to the Agency, as well as to ensure human incident data and the Agricultural Health 

Study (AHS) are part of the problem formulation phase of registration review. Reports of 

adverse health effects allegedly due to a specific pesticide exposure (i.e., an ''incident") are 

largely self-reported and therefore, generally speaking, neither exposure to a pesticide or 

reported symptom (or the connection between the two) is validated or otherwise confirmed. 

Typically, causation cannot be determined based on incident data. However, incident 

information can be an important source of feedback to the Agency: incidents of severe outcome, 

or a suggested pattern or trend among less severe incidents, can signal the Agency to further 

investigate a particular chemical or product. Observational epidemiology studies relate the risk 

of disease, -e.g., cancer, and exposure to an agent such as a pesticide product in the general 

population or specific sub-groups like pesticide applicators. 

II. BACKGROUND 

Metolachlor is a broad spectrum herbicide used for general weed control in many agricultural 

food and feed crops (primarily corn, soybeans and sorghum), and on lawns and turf, ornamental 

plants, trees, shrubs and vines, rights of way, fencerows and hedgerows, and in forestry. The 

emulsifiable concentrate formulation is most commonly used, but granular formulations also are 

available. Ground application is the use method of choice for all sites, although aerial, irrigation, 

and chemigation application methods also are permitted. 

For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease 

Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) 

Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were 

consulted for pesticide incident data on the active ingredient metolachlor (pc codes: 108801, 

1 08800). The purpose of the database search is to identify potential patterns in the frequency 

and severity of the health effects attributed to metolachlor exposure. Metolachlor is included in 

the AHS, and therefore a brief summary of these results are included herein. 

III. RESULTS/DISCUSSION 

a. IDS (Incident Data System) 

OPP's IDS includes reports of alleged human health incidents from various sources, including 

mandatory'Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports from 

across the U.S. and most incidents have all relevant product information recorded. Reports 

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submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in 

the report. 

IDS records incidents in one of two modules: Main IDS and Aggregate IDS: 

o Main IDS contains incidents resulting in higher severity outcomes and provides 

more detail with regard to case specifics. This system stores incident data for 

death, major and moderate incidents, and it includes information about the 

location, date and nature of the incident. Main IDS incidents involving only one 

active ingredient (as opposed to pesticide products with multiple active 

ingredients) are considered to provide more certain information about the 

potential effects of exposure from the pesticide. 

o Aggregate IDS contains incidents resulting in less severe human incidents (minor, 

unknown, or no effects outcomes). These are reported by registrants only as 

counts in what are aggregate summaries. 

For the Main IDS, from January 1, 2006 to May 28,2014, there were 0 incidents reported 

involving metolachlor in the database. 

In Aggregate IDS, from January 1, 2009 to May 28, 2014, there were 0 incident reported 

involving metolachlor in the database. This incident was classified as minor severity. 

b. SENSOR-Pesticides 

The SENSOR-Pesticides database covers 11 states from 1998-2010, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers' 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on 

occupational pesticide incidents, and is of particular value in providing that information. The 

state coordinator at each of the 11 respective state Departments of Health conducts case followup activities such as obtaining medical records to verify symptoms and severity. Using 

standardized protocol and case definitions derived from poison center reporting, the state 

SENSOR-Pesticide coordinator enters the incident information into the state-based system which 

is sent to NIOSH annually to be aggregated. 

A query of SENOSR -Pesticides 1998-2010 identifies a total of 19 cases, stemming from 16 

events, involving metolachlor (pc codes 108801 and 108800). Five ofthese cases involves a 

single active ingredient which will be analyzed for this memo. Two cases were moderate in 

severity and three cases were low in severity. The two moderate severity cases occurred in 

California is 1998 and 2002 respectively, however the case narratives were not provided for 

these two cases. For the remaining three low severity cases, one involved a splash during mixing 

and loading of the product, one case had a rash on his face after working in a treated field, and 

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one case involved drift onto a residential bystander from a field lf4 to Y2 miles away in windy 

conditions. 

Table2. SENSOR-Pesticides 1998-2010 

Health Effects Reported for MetolachJor Cases 

Health Effect Frequency 

Dermal 1 

Ocular 2 

Nervous System 0 

Gastrointestinal I 

Respiratory 2 

Miscellaneous I 

Cardiovascular' I 

Renal 0 

* Cases may report multiple health effects 

c. Agricultural Health Study (AHS) 

The AHS is a high quality, prospective epidemiology study evaluating the potential association 

between pesticide use and various human health outcomes including both cancer and non-cancer 

(e.g., respiratory health) health effects. The AHS includes approximately 90,000 private and 

commercial pesticide applicators and their spouses. If there are AHS findings relevant to a 

particular pesticide going through registration review, the Agency will ensure they are 

considered in the problem formulation/scoping phase of the process and, if appropriate, fully 

reviewed in the risk assessment phase of the process. Metolachlor is a widely used herbicide; in 

the Agricultural Health Study (AHS) 47% of participants report ever-using the pesticides in their 

lifetime (at least one time use). US EPA classifies metolachlor (and S-metolachlor) as a Group C 

"possible" human carcinogen. In an analysis of metolachlor use and various anatomical cancer 

sites (a cohort analysis), authors reported no overall increased risk of all cancers combined 

(relative risk (RR) T3upper v. T1: 1.01 (95% confidence interval ((95% CI) 0.87, 1.30), p trend 

0.98) among 50,193 private and commercial pesticide applicators, nor did authors observe 

significant positive associations with most anatomical cancer sites evaluated including oral 

cavity, colon, alllymphohematopoietic cancers combined and non-Hodgkin lymphoma (NHL) 

(Rusiecki et al., 2006). Authors reported that results did not differ by use of either the lifetime 

exposure day or the intensity-weighted (i.e. , use of PPE) exposure metric, or by use of different 

referent groups (the no exposed or low exposed referent, data not shown). Researchers observed 

an unexpected inverse association with prostate cancer - 40% decreased risk of prostate cancer 

among metolachlor users, but this finding was not observed in early evaluations of prostate 

cancer (Alavanja et al. 2003) and the measure of statistical trend across categories, although 

monotonically decreasing, was not statistically significant (P>0.05). 

1 CA 10861 reported hypertension, no case narrative provided 

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Rusiecki and colleagues reported an increased risk of lung cancer in association with metolachlor 

use; this finding was also reported previously in the cohort (Alavanja et al., 2004). Comparing 

the highest versus lowest metolachlor exposure category, Rusiecki and colleagues observed a 

borderline statistically significantly increased risk of lung cancer 2.37 (95% CI 0.97, 5.82, p for 

trend <0.05); however the measure was imprecise due to a small number of metolachlor exposed 

cancer cases (-10 per category). Authors note that given the timing of pesticide exposure 

information collection, these results reflect use of metolachlor only, and not S-metolachlor (in 

1999 all formulations changed to S-metolachlor). In the previous AHS lung cancer, Alavanja et 

al. (2004) also reported increased risk (odds ratio) of lung cancer in relation to metolachlor use: 

Q 1: 1.0, Q2: 1.6, Q3: 1.2, and Q4:5.0, p for trend 0.002. In this study, authors adjusted for various 

metrics of smoking (former, current, never; pack years) because smoking is a major risk for lung 

cancer, and the results did not change. However authors acknowledge the potential for additional 

residual confounding due to smoking due to the difficulty of measuring this effect accurately in 

lung cancer studies. Both of these AHS lung cancer-metolachlor evaluations were published 

prior to the update of the AHS exposure algorithm which more evenly weights dermal and 

inhalation exposures; therefore, future evaluations will be less biased in this regard, and may 

present a more accurate estimation of potential risk among those exposed. 

There is a molecular epidemiology study within the cohort that provides additional information 

as to the potential carcinogenicity of metolachlor, as well as other pesticides. Telomeres are 

genetic material at the end of chromosomes that reduce in length after each cell division 

eventually triggering cell death. The mechanisms of telomere shortening are similar to suspected 

mechanisms of carcinogenicity and include oxidative stress and inflammation, generally. 

Telomere length has been associated with cancer risk in some studies. In the AHS, authors 

measured relative telomere length (RTV) among 1,234 healthy (non-cancer) male participants in 

the cohort in relation to reported pesticide use (Hou et al., 2013). Authors hypothesized that 

pesticide exposure may affect telomere shortening. The authors reported significant reduction in 

relative telomere length (RTL) in association with lifetime use of metolachlor (RTL 1.24±0.41 to 

1.16± 0.33, p=0.002) (Hou et al., 20 13). It is possible metolachlor and other pesticides may 

influence cancer etiology through telomere length reduction - however this hypothesis has not 

been tested yet within the Study. In another cancer epidemiology study investigating a novel 

hypothesis regarding the mediating role of obesity (measured as body mass index (BMI)), 

Andreotti et al. (20 1 0) reported a modest increased risk of colorectal cancer in relation to 

metolachlor use among those with an elevated body mass index (BMI): RR 1.09 (95% CI 1.04, 

1.15), p=0.02) indicating a possible combined effect of the herbicide exposure through BMI with 

colorectal cancer. These results have not been replicated and the biological mechanisms are 

unclear. Among other anatomical cancer sites investigated in relation to (all) pesticide use, 

metolachlor use was not associated with either pancreatic, colorectal, prostate or breast cancers, 

or was the herbicide use associated with cutaneous melanoma (Alavanja et al., 2003; Andreotti et 

al., 2009; Dennis, Lynch, Sandler, & Alavanja, 2010; Engel et al., 2005; Koutros et al., 2013; 

Lee et al., 2007). 

Metolachlor was among several pesticides included in an exposure assessment study within the 

AHS designed to determine level of track-in or non-intentional pesticide exposure. Results 

indicate the chemical, likely due to its common use in agriculture, is detected in the home 

environment as a result of agricultural use (B. Curwin, Sanderson, Reynolds, Hein, & Alavanja, 

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2002; B. D. Curwin> Hein> Sanderson> Barr> et al., 2005; B. D. Curwin> Hein> Sanderson, 

Nishioka> et al., 2005). Concerning non-cancer health outcomes, Slager and colleagues report a 

slight increased risk of rhinitis in association with the herbicides use> controlling for other farm 

related exposures relating of wheat and corn production (Slager et al., 2009; Slager et al., 20 I 0). 

The Agricultural Health Study has published two papers 2004 and 2006) which associate 

metolachlor with a possible role in lung cancer etiology. Strengths of these findings include the 

study design and sample size> valid and reliable exposure assessment> and control for potentially 

confounding variables including use of other pesticides and smoking. However> authors note that 

several pesticides in addition to this herbicide were linked with lung cancer in the cohort> 

multiple comparison were not adjusted due to lack of method to adjust in non-independent 

exposures data> and residual or uncontrolled confounding due to smoking could have played a 

role. Future studies will utilize the updated AHS exposure algorithm which more accurately 

reflects the influence of inhalation exposures. EPA will continue to examine this literature> 

particularly follow-up studies in the cohort on lung cancer utilized update exposure data and 

exposure algorithm. 

IV. CONCLUSION 

There does not appear to be a concern at this time that would warrant further investigation, since 

there is a low frequency of reported incidents involving metolachlor reported to IDS and 

SENSOR-Pesticides. Research studies within the AHS cohort observed an association between 

metolachlor and lung cancer in two separate evaluations, one in 2004 (Alanvanja) and an 

updated one in 2006 (Rusiecki). The Agency will continue to monitor the incident information 

and if a concern is triggered, additional analysis will be included in the risk assessment. 

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Citations: 

Alavanja, M. C., Dosemeci, M., Samanic, C., Lubin, J., Lynch, C. F., Knott, C., ... Blair, A. (2004). Pesticides 

and lung cancer risk in the agricultural health study cohort. Am J Epidemiol, 160(9), 876-885. doi: 

10.1093/aje/kwh290 

Alavanja, M. C., Samanic, C., Dosemeci, M., Lubin, J., Tarone, R., Lynch, C. F., ... Blair, A. (2003). Use of 

agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort. Am J 

Epidemiol, 157(9), 800-814. 

Andreotti, G., Freeman, L. E., Hou, l., Coble, J., Rusiecki, J., Hoppin, J. A., ... Alavanja, M. C. (2009). 

Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study Cohort. lnt J 

Cancer, 124(10), 2495-2500. doi: 10.1002/ijc.24185 

Andreotti, G., Hou, L., Beane Freeman, L. E., Mahajan, R., Koutros, S., Coble, J., ... Alavanja, M. (2010). 

Body mass index, agricultural pesticide use, and cancer incidence in the Agricultural Health 

Study cohort. Cancer Causes Control, 21(11), 1759-1775. doi: 10.1007/s10552-010-9603-9 

Curwin, B., Sanderson, W., Reynolds, S., Hein, M ., & Alavanja, M. (2002). Pesticide use and practices in 

an Iowa farm family pesticide exposure study. J Agric Saf Health, 8(4), 423-433. 

Curwin, B. D., Hein, M. J., Sanderson, W. T., Barr, D. B., Heederik, D., Reynolds, S. J., ... Alavanja, M. C. 

(2005). Urinary and hand wipe pesticide levels among farmers and nonfarmers in Iowa. 1 Expo 

Anal Environ Epidemiol, 15(6), 500-508. doi: 10.1038/sj.jea.7500428 

Curwin, B. D., Hein, M. J., Sanderson, W. T., Nishioka, M.G., Reynolds, S. J., Ward, E. M., & Alavanja, M. 

C. (2005). Pesticide contamination inside farm and nonfarm homes. J Occup Environ Hyg, 2(7), 

357-367. doi: 10.1080/15459620591001606 

Dennis, L. K., Lynch, C. F., Sandler, D. P., & Alavanja, M. C. (2010). Pesticide use and cutaneous 

melanoma in pesticide applicators in the agricultural heath study. Environ Health Perspect, 

118(6), 812-817. doi: 10.1289/ehp.0901518 

Engel, L. S., Hill, D. A., Hoppin, J. A., Lubin, J. H., Lynch, C. F., Pierce, J., ... Alavanja, M. C. (2005). 

Pesticide use and breast cancer risk among farmers' wives in the agricultural health study. Am 1 

Epidemiol, 161{2), 121-135. doi: 161/2/121 [pii] 

10.1093/aje/kwi022 

Hou, L., Andreotti, G., Baccarelli, A. A., Savage, S., Hoppin, J. A., Sandler, D.P., ... Alavanja, M. C. (2013). 

Lifetime Pesticide Use and Telomere Shortening among Male Pesticide Applicators in the 

Agricultural Health Study. Environ Health Perspect. doi: 10.1289/ehp.1206432 

Koutros, S., Beane Freeman, L. E., Lubin, J. H., Heltshe, S. L., Andreotti, G., Barry, K. H., ... Alavanja, M. C. 

{2013). Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health 

Study. Am J Epidemiol, 177(1), 59-74. doi: 10.1093/aje/kws225 

Lee, W. J., Sandler, D. P., Blair, A., Samanic, C., Cross, A. J., & Alavanja, M. C. R. (2007). Pesticide use and 

colorectal cancer risk in the Agricultural Health Study. International Journal of Cancer, 121(2), 

339-346. doi: 10.1002/ijc.22635 

Rusiecki, J. A., Hou, L., Lee, W. J., Blair, A., Dosemeci, M., Lubin, J. H., ... Alavanja, M. C. (2006). Cancer 

incidence among pesticide applicators exposed to metolachlor in the Agricultural Health Study. 

lnt 1 Cancer, 118(12), 3118-3123. doi: 10.1002/ijc.21758 

Slager, R. E., Poole, J. A., LeVan, T. D., Sandler, D.P., Alavanja, M. C. R., & Hoppin, J. A. (2009~. Rhinitis 

associated with pesticide exposure among commercial pesticide applicators in the Agricultural 

Health Study. Occupational and Environmental Medicine, 66(11), 718-724. doi: 

10.1136/oem.2008.041798 

Slager, R. E., Simpson, S. L., Levan, T. D., Poole, J. A., Sandier, D.P., & Hoppin, J. A. (2010). Rhinitis 

associated with pesticide use among private pesticide applicators in the agricultural health 

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